Canagliflozin Inhibits Human Endothelial Cell Proliferation and Tube Formation
Canagliflozin Inhibits Human Endothelial Cell Proliferation and Tube Formation
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DOI：
10.3389/fphar.2019.00362
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发表时间：
2019-04-16
影响因子：
5.6
通讯作者：
Durante, William
中科院分区：
文献类型：
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作者：
Behnammanesh, Ghazaleh;Durante, Zane E.;Durante, William
最近的临床试验显示，钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂可显著降低2型糖尿病患者的心血管事件，然而，卡格列净增加了截肢率，这是其他SGLT 2抑制剂未观察到的效果。由于内皮细胞（EC）功能障碍可促进糖尿病相关血管疾病和肢体缺血，因此我们假设卡格列净（而非其他SGLT 2抑制剂）可损害EC增殖、迁移和血管生成。用临床相关浓度的卡格列净（而非恩格列净或达格列净）处理人脐静脉EC（HUVEC）可抑制细胞增殖。特别是，10 μ M卡格列净使EC增殖减少约45%。卡格列净对EC生长的抑制发生在无细胞死亡的情况下，并与DNA合成减少、细胞周期停滞和细胞周期蛋白A表达显著降低相关。通过腺病毒介导的基因转移恢复细胞周期蛋白A表达部分挽救了卡格列净治疗的HUVEC的增殖反应。高浓度的卡格列净（50 μ M）适度抑制HUVEC迁移20%，但显着减弱其管形成65%和EC发芽从小鼠睾丸80%。高浓度恩格列净（50 μ M）也观察到HUVEC迁移中度减少20%，而恩格列净和达格列净均不影响HUVEC的管形成。本研究确定卡格列净是人EC增殖和管形成的强效抑制剂。卡格列净的抗增殖作用在没有细胞死亡的情况下发生，部分原因是阻断细胞周期蛋白A的表达。值得注意的是，恩格列净或达格列净未观察到这些作用。卡格列净对EC发挥这些多效性作用的能力可能有助于该药物的临床作用。
Recent clinical trials revealed that sodium-glucose co-transporter 2 (SGLT2) inhibitors significantly reduce cardiovascular events in type 2 diabetic patients, however, canagliflozin increased limb amputations, an effect not seen with other SGLT2 inhibitors. Since endothelial cell (EC) dysfunction promotes diabetes-associated vascular disease and limb ischemia, we hypothesized that canagliflozin, but not other SGLT2 inhibitors, impairs EC proliferation, migration, and angiogenesis. Treatment of human umbilical vein ECs (HUVECs) with clinically relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin, inhibited cell proliferation. In particular, 10 mu M canagliflozin reduced EC proliferation by approximately 45%. The inhibition of EC growth by canagliflozin occurred in the absence of cell death and was associated with diminished DNA synthesis, cell cycle arrest, and a striking decrease in cyclin A expression. Restoration of cyclin A expression via adenoviral-mediated gene transfer partially rescued the proliferative response of HUVECs treated with canagliflozin. A high concentration of canagliflozin (50 mu M) modestly inhibited HUVEC migration by 20%, but markedly attenuated their tube formation by 65% and EC sprouting from mouse aortas by 80%. A moderate 20% reduction in HUVEC migration was also observed with a high concentration of empagliflozin (50 mu M), while neither empagliflozin nor dapagliflozin affected tube formation by HUVECs. The present study identified canagliflozin as a robust inhibitor of human EC proliferation and tube formation. The anti-proliferative action of canagliflozin occurs in the absence of cell death and is due, in part, to the blockade of cyclin A expression. Notably, these actions are not seen with empagliflozin or dapagliflozin. The ability of canagliflozin to exert these pleiotropic effects on ECs may contribute to the clinical actions of this drug.